-nhsoz-r



=4 a nrnrromnncrmm a YL)-4HYDROXY- 3 TQLUENESULFONAMIDQ PHENYL)-EUTANOL-N-0XIDE Eiji ()chiai, '72 Myogaelani-cho, Bnnlryo-ku, Tokyo, Japan, and Ryonosulre Kido, 1679 Karnikeda-cho, lkeda-shi, Osaka Prefecture, Japan v No Drawing. Original application Sept. 21, 1962, Ser. No. 225,386. Divided and" this appiication July 29, 1963, Ser. No.301,692

1 Claim. (Cl. 260-2934) This invention relates to compounds useful in preparations for anti-inflammatory administration and in meth- 0d of producing anti-inflammatory activity in living bodies.

As anti-inflammatory agents, there have been mostly used adrenocorticoids such as cortisone, hydroccrtisone, prednisone and prednisolone. However, these adrenocorticoids generally exhibit undesirable side actions, when continuously administered for a long time. Because of the drawback present in adrenocorticoids, there have been proposed and made available some non-adrenocortical anti-inflammatory agents such as acetylsalicylic acid, gentisic acid, 2 (fi-chloroethyl) 2,3-dihydro-4-oxo-,1,3- benzoxazine, salicylarnide, aminopyrine, phenylbutazone, sulfinpyrazone; quinacrine, chloroquine, hydroxychloroquine, amodiaquin, gold sodium thiosulfate and e-amiuocaproic acid. However, these non-adrenocortical compounds are generally inferior to the said adrenocorticoids in anti-inflammatory activity. Therefore, it has been desired to realize any other non-adrenocortical compounds possessing a high anti-inflammatory activity as Well as the adrenocorticoids. I

- METHOXY- As the results of the pharmacological investigation on a variety of heretofore known or novel quinuclidine compounds derived from a naturally existing cinchona alkaloid, quinine, it has been now discovered that the quinuclidine compounds, corresponding to the following for mula:

CHzCHzOH wherein R is lower alkyl, phenyl or lower alkylphenyl, possesses a high anti-inflammatory activity. [In this connection, it should be understood that there are actually 0 OHzCHzOH T NHSO R C2H5 wherein R has the same significance as designated above. The present invention is primarily concerned with the particular N-oxide of formula Ila, infra.

The production of the quinuclidine compounds I from 3,163,653 Patented Dec. 29, 1964 quinine can be illustrativcly shown by the following scheme:

Quinine CHr-CO d of chloroquine diphosphate, when subcutaneously administered to rats.

N TABLE 11 LiAlH4 5 Edema Inhzbltzon ACflVlly Test NHSO2R #32115 Average edema D inhibition (percent) ose ZII CHzOH N T t d (magi/15g. of T ft d L v es compoun o y imea era minis ra ion CHaO H weight) of formalin (hour) -N HS 0 z-R 0 2H 5 1-3 443 74) Compound Ia 40 39 20 18 it a at 2 wherein R has the same significance as designated above. All the compounds in the above scheme are known and Chloroquine diphosphate ggg i 2 can be prepared in conventional manners [F eidelberger 100 1g 12 13 et al.: J. Am. Chem. Soc., 41, 819 (1919; Ochiai et al.: J. P1181111; J p 101 Ochlal et L hNorE.'Ihe rats1 wee orally petrcatcil witl lilthe teat coilnpgund and "o s i t en subcu ancousy a ministere orrna in. epro uce c eina was i 33 g 5 2 gig: gi 52 measured and compared with that produced without pretreatment.

a w a m V. (1953); Ochiai et al.: Pharm. Bull., 2, 128 (1954); Ishi- {b115, vhe edema lnhlbltwn activity of the cornpound kawa. pharm Bull 6, 71 (1958)] la 18 at least 10 times that of chloroquine diphosphate,

The quinuclidine compounds I possess a high anti-inwhen Orally admmlstered 10 rats" fiarnmatory activity. For instance, the animal test data TABLE In of the quinuclidine compound corresponding to the followin" formula Edema lnlzzbrtzon Actzvlty Test n Avera c edema inhibition CH CHQOI-I N g (percent) CH O -CH- Dose Edema Test compound (m1g)./l5g.of Tiirficdalter adnliinistration producing E o y o c ema pro ucing agent agen NHS 0 z C Ha 0 2 weight) (hour) 1 3 4-0 are shown in Tables I, II, III, IV, V and VI in contrast with some commercially available anti-inflammatory Aminopyrme 50 16 7 n age ts Compound Ia 0.5

Formalin. TABLE I Ammopyrinenh 5 l I Con1poundIo 0..) 8 5 Edema Inhzbztzon Activity Test Aminopyrine. 50

22 10 Compound 1a-... 0.5 D 45 extran. Edema Dose (m'n/ Average 5 producing Test compound kg. of edema Ammopynne 0 9 2 agent body inhibition Compound m (L 5 12 5 weight) (percent) Norm-The rats were subcutaneously pretreated with the test coin- Compound Ia 5 43 pound and then subcutaneously administered the edema producing 1 00 agent. The produced edema was measured and compared with that 5 3 produced without pretreatment. Chloroquine diphosphate--. 128 12 From the above table, it can be said that the compound 20 3 Ia is at least 100 times as effective as aminopyrine in the D tr n com and M 5 48 edema inhibiting action, when subcutaneously admina 1 32 50 istered to rats. Adding to this, it can be also said that 12 they exhibit a total activity, when administered together.

' h 2 Chloroquine diphosp ate 80 22 TABLE IV 20 0 Anti-Inflammatory Effect Histamine Compound Ia g (it) 1 2g Edema producing Formalin Croton agent Chloro nine di hos hate 100 9 q p p T t R /ff /i? t0 C u 11 "0 (35 g- E. III 3. Sem Hm Omp n a 3 3 M compound oibody of l JOdY 1 28 6o weight) weight) 1 5 Ch Omqume dlphosphate 100 1 Chloroquine diphosphatc 97. 5 97. 5

Nora-The rats were subcutaneously pretreated with the test com- Compound 2 pound and then subcutaneously administered the edema producing In the above table, it is shown that the edema inhibition activity of the compound Ia is more than 100 times that No'rE.The test compound was subcutaneously administered to mice. For the comparison of the efiect, there was employed Trypan Blue test.

Thus, the anti-inflammatory efiect of the compound Ia is approximately times that of chloroquine diphosphate, when subcutaneously administered to mice.

TABLE V Granulation Inhibition Activity Test compound was subcutaneously a istered once daily for 6 days. Twenty-four hours after the last administration, the animals were killed and the granulations weighed.

It is clear that the potency of the compound Ia is approximately 8 times that of hydrocortisone acetate in the granulation inhibiting action.

TABLE VI Toxicity in Rats so (mg/kg. of bodyweight) Test compound Subcuta- Orally neously Chloroquine diphosphate 187. 2 v 884 Compound Ia .Q. 34.8 103 From the above table, it can be said that the compound Ia is much more toxic than chloroquine diphosphate, i.e. 5.5 times at the subcutaneous administration and 8 times at the oral administration.

Summarizing the above animal test data, it is concluded that the compound Ia is more toxic than the commercially available anti-inflammatory agent, e.g. ch-loroquine diphosphate, but the former is remarkably more effective than the latter. Thus, the quinuclidine compounds I are the non-adrenocortical anti-inflammatory agents which can be used safely, compared with the heretofore known non adrenocortical anti inflammatory agents.

As disclosed above, the quinculidine compounds I have a relatively high toxicity. However, according to this invention, the toxicity can be decreased by their conversion into the corresponding N-oxides. The quinuclidine-N-oxide compounds II are .novel and can be produced'by subjecting the quinuclidine compounds I to oxidation according to aper se conventional manner. For instance, the quinuclidine compound I is treated with hydrogen peroxide in acetic acidat room temperature to C.) whereby the quinuclidine-N-oxide compound II is prepared. The quinuclidine N-oxide compounds II are less toxic than the quinuclidine compounds I, the former being parallelly less potent than the latter in anti-inflammatory activity. For instance, the animal test data of the quinuclidine-N-oxide compound, corresponding to the following formula:

are compared with that of the in Tables VII and VIII.

quinuclidine compound Ia TABLE VII Edema Inhibition Activity Test Average edema inhibition (percent) Dose (mg./ 7 Test compound kg. of body Time after administration of weight) formalin (hour) Compound la 5.0 43 10 1 Compound Ila 50.0 26 18 12 NOTE.-The rats were subcutaneously pretreated with the test compound and then subcutaneously administered the edema producing agent. The produced edema was measured and compared with that produced without -pre treatment.

TABLE VIH Toxicity in Mice LDsn (mg/kg. of

venously Compound Ia 2.0

Compound Ila 42. 3

Thus, the quinuclidine-N-oxide compounds II are less toxic and less potent than the quinuclidine compounds I. But, they are still remarkably active, compared with the heretofore known anti-inflammatory agents. Therefore, they are useful as non-adrenocottical anti-inflammatory agents which can be employed safely, too.

The quinuclidine-N-oxide compounds II may also be employed in the form of their salts with non-toxic acids. As the salts, there may be exampled those with hydrochloric, hydrobromic, sulfuric, acetic, lactic, succinic, tartaric, citric, ascorbic, cinnamic, salicylic or 4-arninosalicylic acid. Of these salts, the salicylic acid addition salt is particularly preferred in easy crystallizability.

The active medicaments, e.g. the quinuclidine compounds II or their salts with non-toxic acids, are administered in dosage unit form, as carried by a suitable pharmaceutical carrier, to living bodies particularly for the relief of rheumatism. Normally, the preparation is orally administered, although they are just as effective whenotherwise administered. They may be administered in various dosages such as 3, 5, 10, 15, 20, 25 or 30 milligrams, although the unit dosage range may vary more broadly from about 1 toabout milligrams and preferably from about 5 to about 30 milligrams. They may be added to or otherwise used with various pharmaceutical carriers. By way of exemplification, various solid carriers may be employed such as lactose, mannitol, cornstarch, talc and magnesium stearate as well as other tableting aids and fillers. If desired, some other ingredients such as hydrocortisone, prednisolone, aminopyrine, chloroquine and the like may be mixed with the said active medicaments. The medicinal mixture may then be tableted or encapsulated in a hard gelatine' capsule, depending on the commercial unit form desired. Ordinarily tableting is preferred. The amount of carrier or diluent may vary, according to tablet size desired or Whether the dosage is made up in encapsulated form, from 7 zero amount to the maximum amount consistent with the practical limits of bulk for a dosage unit. Normally the carrier with which the medicament is mixed does not exceed about 300 to about 500 milligrams.

The following are typical examples of preparations embodying the present invention.

EXAMPLE 1 Kilograms 4 (3-ethylquinuelidin-8-yl) 4 hydroxy 3 (2- toluenesulfonamido-S-methoxyphenyl-butanol 1.00 Lactose 8.47 Cornstarch 3.48 Magnesium stearate 2.60

The foregoing are mixed and granulated with a acacia solution and dried. The granule is forced through a 16 mesh screen, and thereafter is mixed with the following:

Kilograms Sodium lauryl sulfate 0.20 Magnesium stearate 1.00

Amylum solani, q.v. to 37.50

This mixture is tableted in the usual way to give 100,000 tablets. Each tablet weighing 37.5 milligrams contains 12.73 milligrams of the active ingredient (equal to 10 milligrams of the free base).

EXAMPLE 3 To a solution of 4-(3-ethylquinuclidin-8-yl)-4-hydroxy- 3- 2-toluenesulfonamido-5 -methoxyphenyl -butano1 (300 mg.) in glacial acetic acid (2.5 ml.), there is added 30% hydrogen peroxide (0.3 ml.-), and the resultant solution is allowed to stand for 24 hours at room temperature. Then, 30% hydrogen peroxide (0.3 ml.) is further added to the solution and allowed to stand for 48 hours at room temperature. The reaction mixture is adjusted with 10% aqueous sodium hydroxide to alkalinity and shaken with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the chloroform layer, the residue is crystallized from a mixture of acetone and ether to give 4-(3- ethylquinuclidin-8-yl) 4 hydroxy '3 (Z-toluenes-ulfonamido-S-methoxyphenyl) butanol-N-oxide mg.) as white pillars melting at 228 C.

AIZGIYSI S-Cfllcd. for C H O N St C, H, N, 5.41. Found: C, 63.05; H, 7.64; N, 5.44.

The present application is a division of copending application, Serial No. 225,386, filed September 21, 1962.

What is claimed is:

The compound of the formula:

orr cmo H 'r No references cited. 

